Prescription drug products stability and expiration dates*

UTMB/NASA-JSC Aerospace Medicine Grand Rounds

Houston, TX
October 27, 2009

Mansoor A. Khan, R.Ph., Ph.D.

Director, FDA/CDER/Division of Product Quality Research Views are my own and does not represent the official policy of the Agency
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Outline
Introduction to FDA and DPQR Drug product shelf life & expiration date Shelf-Life Extension Program (SLEP) Repackaged products

Food and Drug Administration

ORA

CDER
Drugs

CBER
Biologics

CDRH

CVM

CFSAN
Food Cosmetics

NCTR

Devices Veterinary

Combination products
Field Laboratories Office of Biotech Laboratories Office of Testing and Research Laboratories
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Research in DPQR

DS
Analytical
Methods Excipients Formulation variables Process variables Mechanistic evaluations Optimization & ANN procedures

Cell Culture PK/ Bioavailability

DP

Characterization Stability

Nanoparticles
Liposomes SR/MR TDDS Nasal Pulmonary Fast disintegration Solid dispersion

Physical

Chemical

Mixing Milling Granulation Drying Compression Coating Packaging

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Stability, shelf-life, and expiration date

Drug substance and products could degrade by oxidation, hydrolysis, racemization etc. Factors such as temperature, humidity, light, pH, ionic strength, buffer strength could enhance the degradation. It is expected that a well designed formulation and packaging protects the product from degradation A shelf-life generally means a product will retain approved specs in the final packaged container, in stated storage conditions, when tested by validated methods An expiration date must be placed on container label (21 CFR 201.17).
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Levothyroxine Sodium
I HO I ONa H I O I NH2 x H2O O

Levothyroxine Stability Indicating Method*

T0 T2 T3 DIT
275

Peak area

175

75

-25 0

Tyr

10 Time (min)

Theo

MIT

15

T4

20

International Journal of Pharmaceutics, 360:77-82, 2008.

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How is Shelf Life Established?

Applicant conducts systematic stability testing (21 CFR 211.166) according to a prescribed protocol
Select samples from representative batches Store samples at defined storage conditions*
Accelerated (40C/75% relative humidity or RH) Long-term (25C/60% RH) Intermediate (30C/65% RH), if needed

*(Other stress conditions, e.g., light, acid, base, oxidant, for

one-time testing)

Pull samples at predetermined intervals

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How is Shelf Life Established?

Test samples for product attributes susceptible to change during storage and shipping and likely to influence quality, safety, and/or efficacy
Physical attributes, e.g., appearance, particle size Chemical attributes, e.g., assay, degradants, pH In vitro drug release rate, e.g., dissolution Biological, e.g., bioassay, and microbiological attributes

Analyze data for each attribute as a function of time against proposed acceptance criteria Determine if the proposed shelf life can be supported by available data
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How is Shelf Life Established?

Perform regression analysis (if needed)
110 Raw data Regression line Two-sided 95% confidence limits Lower acceptance criterion

105

% Label Claim

100

95

90

85 0 1 2 3 4 5
10

Time (years)

Stability Test Attributes

Solid Orals Potency Assay Impurities Dissolution Water Content Appearance Injectables Potency Assay Impurities Preservatives pH Appearance Color Particulates

Powders Potency Assay pH Water Content Appearance

Creams/Ointments Potency Assay pH Appearance

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Gabapentin
Example of a drug product impurity
H2N COOH
HN C=O

Lactam impurity Gabapentin J. Pharm and Biomed. Analysis, 2008, 46, pp. 181-186. * Laboratory efforts: Understand all the variables and their interactions that enhance the impurity level. DOE experiments to obtain a design space of a unit operation. Drying and granulation process monitored by Near IR and chemical imaging.

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Granule Potency at 40 oC/75% RH 110 105 100

Potency (% claim)

95 90 85
PVP-W PVP-A xPVP-A HPC-A Polx-A

80 75 70 0 2 4 6 8 Time (weeks)

xPVP-W HPC-W Polx-W

10

12

14
13

RC-A formation in Granules stored at 40 C/75% RH

2.4
PVP-W PVP-A xPVP-A HPC-A Polx-A

Related Compound A (% w/w)

2.0 1.6

xPVP-W HPC-W Polx-W

1.2 0.8 0.4 0.0 0

USP limit for RC-A

6 8 Time (weeks)

10

12

14
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RC-A formation in Tablets stored at 40 oC/75% RH

3.6 3.2
Related Compound A (% w/w)
PVP-W xPVP-W PVP-A xPVP-A HPC-A Polx-A

2.8 2.4 2.0 1.6 1.2 0.8 0.4 0.0 0 2

HPC-W Polx-W

USP limit for RC-A

6 8 Time (weeks)

10

12

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SLEP: Program Operation

Drug Lot Stored in Military/SNS/VA Stockpile Samples
SLEP Military/ SNS/VA Contact

Samples
FDA Field Lab Testing

New Expiration Date

Samples Test Results

FDA SLEP Coordinator

Data Evaluation, Analysis, and Estimations of New Expiration Date

Tests/Test methods/Location of standards/procedures/research (when needed)

FDA CDER Chemist Analysis

Lyon et. al., J. Pharm. Sci., 2006, 95, 1549-1560.

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Group 1A: Products with No Failures ( 10 lots tested) Drug Product Amoxicllin Sodium Ciprofloxacin Diphenhydramine HCl Doxycycline Hyclate Doxycycline Hyclate Halothane Mannitol Morphine Sulfate Naloxone HCl Oxacillin Sodium Potassium Iodide Sodium Bicarbonate Sodium Chloride Sodium Nitrite Sodium Thiosulfate Dosage Form Tablets Tablets Syringe-Needle a Capsules b Powder b Liquid Injection-Solution Syringe-Needle c Injection-Solution Powder Tablets d Injection-Solution Irrigation e Injection-Solution Injection-Solution Tested 21 242 12 13 31 12 10 13 10 13 12 37 16 10 14 Mean 23 55 76 50 27 67 66 89 77 56 69 55 72 89 131 17

Cefoperazone Sodium Cephapirin Sodium Cimetidine HCl Dextrose (5%) Flurazepam HCl Morphine Sulfate Ophthalmic Irrigating Pancuronium Bromide Ringers, Lactated and Dextrose Sodium Chloride Sodium Polystyrene Sulfonate Sulfadiazine Silver Tetracycline HCl Thiopental Sodium

Powder Powder Injection-Solution c Injection-Solution Capsules Autoinjector d Solution Injection-Solution Injection-Solution Injection-Solution e Powder Cream Capsules Powder

4 13 7 22 3 3 6 13 13 41 3 37 11 12

46 74 42 65 35 32 52 79 53 50 55 57 50 54

Assay Potency Assay Assay; Appearance i Appearance Degradant Low pH Assay (1) Assay k ; Assay, Appearance Assay; pH Water Content High pH & Assay Dissolution ; Degradant Low pH ; Appearance 18

 Current DoD participants

US Army US Air Force US Navy US Marines

SLEP Participants

CDC/Strategic National Stockpile (SNS) since 2004 Dept. of Veterans Affairs (VA) since 2005 Only Federal agencies that sign an MOA with DOD may participate in SLEP

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SLEP Challenges
Protocols/Procedures References standards Specialized equipment Lab research when needed Record keeping Knowledge Management
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FDA Shelf Life Research Example

Force-Displacement
Cap Crushing Strength
Empty Capsule Cap

5 4
Force (Kg)

1975 1999
Hardness (kp)

2004

3 2 1 0 0.0 0.5 1.0 1.5 2.0 Distance (mm) 2.5 3.0 3.5

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 1975

Tablet Hardness Tester (n = 10)

F or c e

1999 Manufacture Year

2004

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Research Lessons Actual shelf life may be much longer than Learned

indicated by expiration date on the product original label. Shelf life varies greatly between lots. Continued testing and systematic evaluation is required to ensure product quality. Analyses of the successes and failures can help in applying this information to new product development.

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Repackaged Product Background

The draft guidance, CPG 7132.b11, specifies conditions where it may be possible to assign up to 12 months expiration dating to non-sterile solid and liquid oral dosage form drug products repackaged into unit dose containers for Class A, without conducting new stability studies. According to USP,
a unit dose container is designated Class A if not more than 1 of 10 containers exceed 0.5 mg/day in moisture permeation rate, and none exceeds 1 mg/day. a unit dose container is designated Class B if not more than 1 of 10 containers exceed 5 mg/day in moisture permeation rate, and none exceeds 10 mg/day.
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Two repackaging firms say a draft FDA guidance should be revised to allow one year dating on open dose packages using Class B material. ('http://www.fdaweb.com/start.php?sa=v&aid=D51 00826&cate=&stid=4LnsBWacYRN0k') FDA Webview, Sept 12, 2005

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Unit Dose Products Selected

Ranitidine HCl Syrup, 15 mg/mL Metoprolol tartrate tablets, USP 50 mg Phenytoin sodium suspension, USP 125 mg/5 mL Gabapentin capsules, 300 mg Furosemide tablets, USP, 40 mg
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Original packaging tablets Time 0

Original packaging tablets Stored at 25C 60%RH for 4 Weeks Original packaging tablets Stored at 40C 75%RH for 4 Weeks

Repackaged tablets Stored at 25C 60%RH for 4 Weeks Repackaged tablets Stored at 40C 75%RH for 4 Weeks

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Overall Conclusions
Drug product degrade by several different type of reactions It is important to monitor several product attributes in addition to the amount of main drug The stability of a product beyond expiration is not evaluated. Some product could be dangerous if used after expiration SLEP program is restricted to certain federal agencies at this time Repackaged metoprolol tartrate tablets Product integrity compromised at accelerated conditions. Repackaged Phenytoin Sodium Suspension Product uniformity, potency, and dissolution compromised at initial time point itself Repackaged Ranitidine HCl Syrup, Furosemide Tablets, and Gabapentin Capsules no stability issues in the conditions of experiment
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